Pre-processing and QC - brain structure data:

Models:
- GLM for unilatearal brain phenotypes - LME for bilateral brain phenotypes where measures of hemisphere were treated as repeated measures - No hemishphere interactions on association between DNAm score and bilateral phenotype observed
Covariates: - Sex - Age - Age^2 - BMI - UKB imaging assessment centre - ICV (only for measures of brain volume)
Multiple comparision correction: FDR - n = number of brain structure phenotypes per imaging subcategory

Sample demographics

Groups

Participants with complete data (n females/males) (proportion female)

Cases (n females/males) (proportion female)

Mean age in female cases/controls (Years)

Mean age in male cases/controls (Years)

Mean BMI in female cases/controls (Years)

Mean BMI in male cases/controls (Years)

MDD

13018/12192 (52%)

4238/2229 (66%)

61.58/63.74 *

62.26/65.26 *

26.89/25.75 *

27.63/26.79 *

CP

21812/19390 (53%)

8540/6426 (57%)

63.06/63.41 *

64.59/64.59

26.96/25.48 *

27.5/26.67 *

CP+MDD+

12934/12104 (52%)

2158/960 (69%)

61.26/63.77 *

62.16/65.21 *

27.77/25.35 *

28.01/26.54 *

CP+MDD-

12934/12104 (52%)

2879/2869 (50%)

61.87/63.77 *

62.3/65.21 *

25.97/25.35 *

27.31/26.54 *

CP-MDD+

12934/12104 (52%)

2047/1247 (62%)

63.63/63.77

65.31/65.21

26.57/25.35 *

27.41/26.54 *

CP-MDD-

12934/12104 (52%)

5850/7028 (45%)

63.77/63.77

63.77/65.21

25.35/25.35

25.35/26.54

Main Results - Brain structures

Effect size graph - Comorbidity in full sample

P-value graph - Depression - full sample
## Warning: Using `size` aesthetic for lines was deprecated in ggplot2 3.4.0.
## ℹ Please use `linewidth` instead.
## This warning is displayed once every 8 hours.
## Call `lifecycle::last_lifecycle_warnings()` to see where this warning was
## generated.

P-value graph - Depression - sex-stratified sample
## Warning in get_plot_component(plot, "guide-box"): Multiple components found;
## returning the first one. To return all, use `return_all = TRUE`.

P-value graph - Chronic Pain Status - full sample

P-value graph - Chronic Pain - sex-stratified sample
## Warning in get_plot_component(plot, "guide-box"): Multiple components found;
## returning the first one. To return all, use `return_all = TRUE`.

Cortex atlas map

Subcortical atlas map

Brain map: chronic pain
## merging atlas and data by 'region'
## merging atlas and data by 'region'
## merging atlas and data by 'region'
## merging atlas and data by 'region'

Brain map: depression
## merging atlas and data by 'region'
## merging atlas and data by 'region'
## merging atlas and data by 'region'
## merging atlas and data by 'region'

Supplementary Results

Effect size graph - Chronic pain status in full sample

Effect size graph - Chronic pain status in sex-stratified samples

Effect size graph - Probable Recurrent Major Depressive Disorder in full smaple

Effect size graph - Probable Recurrent Major Depressive Disorder in sex-stratified sample

Effect size graph - Balanced datasets

Number of significant hits

sum(res_comorbidity_brain_structure_all$p.adjust < 0.05)
## [1] 211
sum(res_comorbidity_brain_structure_female$p.adjust < 0.05)
## [1] 105
sum(res_comorbidity_brain_structure_male$p.adjust < 0.05)
## [1] 5
sum(brain_structure_CP_all$`Adjusted p-value < 0.05` == "Yes")
## [1] 51
sum(brain_structure_CP_female$`Adjusted p-value < 0.05` == "Yes")
## [1] 39
sum(brain_structure_CP_male$`Adjusted p-value < 0.05` == "Yes")
## [1] 11
sum(brain_structure_MDD_all$`Adjusted p-value < 0.05` == "Yes")
## [1] 29
sum(brain_structure_MDD_female$`Adjusted p-value < 0.05` == "Yes")
## [1] 30
sum(brain_structure_MDD_male$`Adjusted p-value < 0.05` == "Yes")
## [1] 1

Number of significant hits - balanced vs unbalanced

cat("Unbalanced comorbidity:")
## Unbalanced comorbidity:
sum(res_comorbidity_brain_structure$p.adjust < 0.05)
## [1] 271
sum(res_comorbidity_brain_structure_female_save$p.adjust < 0.05)
## [1] 105
sum(res_comorbidity_brain_structure_male_save$p.adjust < 0.05)
## [1] 5
cat("Balanced comorbidity:")
## Balanced comorbidity:
sum(res_comorbidity_brain_structure_balanced_f$p.adjust < 0.05)
## [1] 54
sum(res_comorbidity_brain_structure_balanced_m$p.adjust < 0.05)
## [1] 6
cat("Unbalanced CP:")
## Unbalanced CP:
sum(brain_structure_CP_female$`Adjusted p-value < 0.05` == "Yes")
## [1] 39
sum(brain_structure_CP_male$`Adjusted p-value < 0.05` == "Yes")
## [1] 11
cat("Unbalanced MDD:")
## Unbalanced MDD:
sum(brain_structure_MDD_female$`Adjusted p-value < 0.05` == "Yes")
## [1] 30
sum(brain_structure_MDD_male$`Adjusted p-value < 0.05` == "Yes")
## [1] 1